The role of neuromelanin in dopaminergic neuron demise and inflammation in idiopathic Parkinson's disease

For a very long time, the main focus in Parkinson’s disease (PD) research was the
loss of neuromelanin-containing dopaminergic neurons from the substantia nigra (SN)
of the midbrain - the key pathological feature of the disease. However, the association
of neuronal vulnerability and neuromelanin presence has not been a common study
subject. Recently, cells other than neurons also gained attention as mediators of PD
pathogenesis. There are indications that glial cells undergo disease-related changes,
however, the exact mechanisms remain unknown.
In this thesis, I aimed to explore the contribution of every cell type of the midbrain
to PD using single-nuclei RNA sequencing. Additionally, the goal was to explore their
association to PD risk gene variants. As we identified microgliosis as a major mechanism
in PD, we further extended our research to microglia. We sought to investigate the
relation of microglia and neuromelanin. Thus, we aimed to, by means of immunohistochemical
staining, imaging and laser-capture microdissection-based transcriptomics,
elucidate this association on a single-cell level.
This work resulted in the first midbrain single-cell atlas from idiopathic PD subjects
and age- and sex-matched controls. We revealed SN-specific microgliosis with GPNMB
upregulation, which also seemed to be specific to the idiopathic form of the disease.
We further observed an accumulation of (extraneuronal) neuromelanin particles
in Parkinson’s midbrain parenchyma, indicative of incomplete degradation. Moreover,
we showed that GPNMB can be alleviated in microglia in contact with neuromelanin.
Taken together, we provide evidence of a GPNMB-related microglial state as a disease
mechanism specific to idiopathic PD, and highlight neuromelanin as an important
player in microglia disease pathology. Further investigations are needed to understand
whether the modulation of neuromelanin levels could be relevant in the context of PD
therapy.